Metabolic syndrome, insulin resistant diabetes, and cardiovascular disease are currently major contributors to the burden of heath management in the US and other developed countries. The etiology of these diseases is still poorly understood. A growing body of evidence suggests dysregulation of fatty acid metabolic pathways is a major causative factor. Currently, only a limited number of drugs are available to combat these diseases and it is clear new drugs, which more narrowly target the metabolic pathways involved, are required. In the present work, we seek to continue our methods development project aimed at identifying and characterizing chemical compounds that prevent fatty acid transport as a method to limit dietary fat absorption into cells and tissues that are susceptible to toxic effects of excessive fatty acids including pancreas, liver and muscle. We also expect some of the compounds we identify may be employed to specifically reduce intestinal absorption as a primary step in preventing absorption of excess fat calories. A long-term goal is to identify compounds that distinguish between classes of fatty acids to prevent cellular uptake and accumulation of saturated and trans- unsaturated fatty acids, while permitting the absorption of polyunsaturated fatty acids. The present proposal follows from our work to develop and test methods for high throughput screening to identify inhibitors of fatty acid uptake dependent upon the human fatty acid transport proteins (FATP). In the previous funding period we targeted human FATP expressed in the yeast Saccharomyces cerevisiae to establish and test methods to screen for fatty acid uptake inhibitors in a high throughput format. We now plan to extend these studies to refine our screening methods by employing various model systems that target specific organs to characterize compounds identified in a preliminary screen of 100,000 compounds for usefulness as lead drugs targeting fatty acid uptake in liver and intestine and to test the hypothesis some atypical antipsychotics cause metabolic dyslipidemia by inhibiting fatty acid uptake into specific cell types. PUBLIC HEALTH RELEVANCE: This research project addresses the need for pharmaceuticals to combat obesity and chronically high blood triglycerides and free fatty acids that result in diseases such as metabolic syndrome, cardiovascular disease and type 2 diabetes. These studies are a continuation of a methods development project aimed at selecting small compounds useful to inhibit fatty acid uptake into cells so that these toxic compounds cannot cause cell dysfunction and disease. Very few such drugs are currently in clinical use.